Professor Carl Smythe

Professor Carl Smythe

Professor of Cell Biology
Director: Biological Mass Spectrometry Facility
Department of Biomedical Science
The University of Sheffield
Western Bank
Sheffield S10 2TN
United Kingdom

Room: C106 Addison building
Telephone: +44 (0) 114 222 4643
Email: c.g.w.smythe@sheffield.ac.uk

CMIAD


Cell Biology and Cancer

General

Brief career history

  • 2002 – present: Professor of Cell Biology, Department of Biomedical Science, University of Sheffield
  • 2004 – 2006: Head of Department, Department of Biomedical Science, University of Sheffield
  • 1992 – 2002: Principal Investigator at MRC Protein Phosphorylation Unit, University of Dundee
  • 1989 – 1992: American Cancer Society Senior Research Fellow, University of California, San Diego
  • 1985 – 1989: British Diabetic Association postdoctoral research assistant at MRC Protein Phosphorylation Group at University of Dundee
  • 1981 – 1985: PhD Department of Biochemistry, Trinity College, University of Dublin

Research interests

Chromosome Integrity

Chromosomes in eukaryotes control their environment to ensure that genomic integrity is maximised. We are interested in understanding mechanisms of genomic integrity operating at the molecular and cellular level, and determining the consequences when they fail.

Full publications

Research

Cellular surveillance systems and their role in healthy aging

Research in our laboratory uses molecular cell biology approaches to understand quality control or surveillance mechanisms that operate in cells to ensure fidelity of function, the consequences when they fail, and how they may be exploited to ameliorate disease. Examples include the replication checkpoint, which operates to ensure that cells experiencing replication stress, can evoke appropriate DNA damage responses, reschedule cell cycle events, or initiate apoptosis, and quality control systems regulating processes involving RNA homeostasis, such as nonsense-mediated decay (NMD), histone mRNA decay (HD), and telomere stability.

We utilise a variety of disease cell models in mechanistic studies and utilise whole genome and new chemical entity (NCE) screening together with mass spectrometry and imaging techniques, coupled with in vitro assays, to synergistically probe both biological and NCE function.

Our chemical biology work focuses on exploring the use of ruthenium co-ordination complexes to explore novel chemical space affecting pathways of interest, as well as novel indole polycyclic derivatives that block NMD.

Our focus is to identify potential new therapeutic targets in relevant disease models, and our work on the replication checkpoint has identified a number of proteins and /or pathways which are of interest.

Figure 1

Future directions

A key focus concerns the functional characterisation of the DNA /RNA helicase Upf1 which acts pleiotropically to regulate NMD, HD and telomere integrity. We have identified a novel NMD inhibitor which, importantly, does not affect histone mRNA regulation or telomere integrity. We aim to utilise our expertise in genomic integrity and mass spectrometry to identify the target of this inhibitor as a potential therapeutic strategy for the treatment of nonsense mutation-associated disease.

Funding

  • Cystic Fibrosis Trust
  • Yorkshire Cancer Research
  • Royal Thai Higher Education Commission
  • Malaysia Trust Council (Majlis Amanah Rakyat)

Key collaborators

  • Prof Iain Coldham, Dept of Chemistry, University of Sheffield
  • Dr James Thomas, Dept of Chemistry, University of Sheffield
  • Dr Sarah Danson, Dept of Oncology, University of Sheffield
  • Dr Ferdinando Di Cunto, Department of Genetics, Biology& Biochemistry, University of Torino.
Teaching

Undergraduate and postgraduate taught modules

Level 1:

  • BMS109 Pathobiology

Level 2:

  • BMS238 Cell and Molecular Biology

Level 3:

  • BMS379 (Coordinator)
  • BMS349 Extended Library Project

Masters (MSc):

  • BMS6057 Cancer Biology (Coordinator)
Opportunities

PhD Studentship Project

Novel genes required for checkpoint control and their role in colo arectal cancer

Co-Supervisor: Dr Mark Collins

Funding status: Awaiting funding decision/Possible external funding – find out more on our funding webpage.

Project Description

Background

Healthy aging is frequently affected by the onset of cancers. One in three of us will be affected over our lifetime, and 50% will have significantly reduced lifespan as a consequence. Cell cycle checkpoint genes are often mutated in cancers, while paradoxically, in appropriate circumstances, they may be attractive targets for rational drug design.

Our laboratory was one of the first labs to identify the significance of the Chk1 gene product in checkpoint control and have a significant interest in novel therapeutics and their identification. Colorectal cancer remains a significant challenge, often due to late presentation of symptoms and Chk1 inhibitors are currently in clinical trials for a subset of colorectal cancers. Recently we have undertaken a genome-wide siRNA screen in colorectal cancer cells to identify previously unknown checkpoint pathway genes in order to identify novel potential therapeutic targets. As a result we have identified novel genes whose roles in checkpoint regulation are completely unknown.

Aims

The aims of this project is to gain an understanding of the cellular function of one novel gene, which we have called MiCatS, in cellular checkpoint control. MiCatS-deficient cells appear to be unable to respond to cellular signalling pathways that indicate the presence of replication stress. This project will focus on developing an understanding of how MiCatS interferes with regulatory gene networks controlling genome integrity. Techniques: These will include a range of molecular cell biology techniques, tissue culture, confocal fluorescence microscopy, protein expression and functional characterisation approaches including proteomics, quantitative PCR, siRNA-mediated knockdown of gene expression, and immunoblotting.

References

(1) Feijoo, C., Hall-Jackson, C., Wu, R., Jenkins, D., Gilbert, D., and Smythe, C (2001). Activation of mammalian Chk1 during DNA replication arrest: a role for Chk1 in the intra-S phase checkpoint monitoring replication origin firing. The Journal of Cell Biology, 154(5), 913–924.

(2) Bowen, E., (2015). PhD Thesis. “A genomic screen for the identification of novel components of the S phase checkpoint”, University of Sheffield.

Keywords: Cancer / Oncology, Cell Biology / Development, Molecular Biology

Contact information

For informal enquiries about the project or application process, please feel free to contact me.

For further information about projects within the department and how to apply, see our PhD Opportunities page:

PhD Opportunities

Selected publications

Journal articles